Selective hydroxamate based mmp inhibitors

ABSTRACT

The present invention provides a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     said compound is inhibitor of MMP-9, and/or MMP-12 and/or MMP-13, and thus can be employed for the treatment of a disorder or disease characterized by abnormal activity of MMP-9, and/or MMP-12 and/or MMP-13. Accordingly, the compound of formula (I) can be used in treatment of disorders or diseases mediated by MMP-9, and/or MMP-12 and/or MMP-13. Finally, the present invention also provides a pharmaceutical composition.

The present invention relates to novel compounds that are useful asinhibitors of matrix metalloproteinases such as matrix metalloproteinase9 (MMP-9), matrix metalloproteinase 12 (MMP-12) and matrixmetalloproteinase 13 (MMP-13).

In one aspect, the present invention provides a compound of formula (I)

Wherein

R₁ is cyano, alkyl, R₄—O—, R₅—C(O)NH—, or R₆C(O)—, wherein R₄, R₅ and R₆are independently alkyl or aryl each of which is optionally substitutedby one to five substituents selected from the group consisting of(C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy and aryl;

R₂ is alkyl, aryl-alkyl-, or heteroaryl-alkyl-, heterocyclyl-alkyl, ormono-alkylamino-alkyl, di-alkylamino-alkyl; and

R₃ is alkyl; or cycloalkyl

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (I),wherein R₁ is cyano, (C₁-C₇)alkyl, R₄—O—, R₅—C(O)NH—, or R₆C(O)—,wherein R₄, R₅ and R₆ are independently (C₁-C₇)alkyl, phenyl, biphenyl,naphthyl, or tetrahydronaphthyl each of which is optionally substitutedby one to five substituents selected from the group consisting of(C₁-C₇)alkyl, halo, hydroxyl and (C₁-C₇)alkoxy; R₂ is (C₁-C₇)alkyl,(C₆-C₁₀)aryl-(C₁-C₇)alkyl, (5-9 membered) heteroaryl-(C₁-C₇)alkyl, (5-9membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

Also more preferably, the present invention provides the compound offormula (I), wherein R₁ is (C₁-C₇)alkyl, R₄—O, R₅—C(O)—NH—, or R₆C(O)—,wherein R₄, R₅ and R₆ are independently (C₁-C₇)alkyl; R₂ is(C₁-C₇)alkyl, (C₆-C₁₀)aryl-(C₁-C₇)alkyl, or (5-9 membered)heteroaryl-(C₁-C₇)alkyl, (5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

In another embodiment, the present invention provides the compound offormula (I), wherein

R₁ is cyano, (C₁-C₇)alkyl, amino, R₄—O—, (C₁-C₇)alkyl-NHC(O)—,R₅—C(O)NH—, R₆C(O)—, R₉—C(O)—O— or R₁₀—O—(O)—, wherein

R₄, R_(6,) R_(9,) and R₁₀ are independently hydrogen, (C₁-C₇)alkyl,mono- or di-(C₁-C₇)alkylamino or aryl each of which is optionallysubstituted by one to five substituents selected from the groupconsisting of (C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy and aryl;

R₅ is hydrogen, (C₁-C₇)alkyl or (R₇)(R₈)N—;

R₇ and R₈ are independently hydrogen, (C₁-C₇)alkyl, oraryl-(C₁-C₇)alkyl;

R₂ is hydrogen, or (C₁-C₇)alkyl which is optionally substituted by oneto three substituents selected from the group consisting of(C₁-C₇)alkyl, hydroxy, aryl, heterocyclyl, heteroaryl,(C₁-C₇)alkyl-O—C(O)—, di-(C₁-C₇)alkylamino-C(O)—, wherein each of aryl,heterocyclyl, and heteroaryl is further optionally substituted by(C₁-C₇)alkyl; or

R₃ is (C₁-C₇)alkyl, or cycloalkyl;

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (I),wherein

R₁ is (C₁-C₇)alkyl, R₄—O—, or R₅—C(O)NH—, wherein R₄ is (C₁-C₇)alkyloptionally substituted by one to three halo, R₅ is hydrogen ormono-(C₁-C₇)-alkylamino;

R₂ is (C₁-C₇)alkyl optionally substituted by (C₁-C₇)alkyl-O—C(O)—,di-(C₁-C₇)alkylamino, or hydroxy; or

R₂ is aryl-(C₁-C₇)alkyl-, heteroaryl-(C₁-C₇)alkyl-,heterocyclyl-(C₁-C₇)alkyl, wherein said heterocyclyl is optionallysubstituted by (C₁-C₇)alkyl; and

R₃ is (C₁-C₇)alkyl; or a pharmaceutically acceptable salt thereof; or anoptical isomer thereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (I),wherein

R₁ is (C₁-C₇)alkoxy;

R₂ is (C₁-C₇)alkyl;

R₃ is (C₁-C₇)alkyl.

Preferably, the present invention provides the compound of formula (I),wherein

R₁ is (C₁-C₇)alkoxy;

R₂ is (5-9 membered) heteroaryl-(C₁-C₇)alkyl;

R₃ is (C₁-C₇)alkyl.

In another aspect, the present invention provides the compound offormula (II)

Wherein

R₁ is cyano, alkyl, R₄—O—, R₅—C(O)NH—, or R₆C(O)—, wherein R₄, R₅ and R₆are independently alkyl or aryl each of which is optionally substitutedby one to five substituents selected from the group consisting of(C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy and aryl;

R₂ is alkyl, aryl-alkyl-, heteroaryl-alkyl-, heterocyclylalkyl, ormono-alkylamino-alkyl, di-alkylamino-alkyl; and

R₃ is alkyl; or cycloalkyl;

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (II),wherein R1 is cyano, (C₁-C₇)alkyl, R₄—O—, R₅—C(O)NH—, or R₆C(O)—,wherein R₄, R₅ and R₆ are independently (C₁-C₇)alkyl, phenyl, biphenyl,naphthyl, or tetrahydronaphthyl each of which is optionally substitutedby one to five substituents selected from the group consisting of(C₁-C7)alkyl, halo, hydroxyl and (C₁-C₇)alkoxy; R₂ is (C₁-C₇)alkyl,(C₆-C₁₀)aryl-(C₁-C₇)alkyl, (5-9 membered) heteroaryl-(C₁-C₇)alkyl, (5-9membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

Also more preferably, the present invention provides the compound offormula (II), wherein R₁ is (C₁-C₇)alkyl, R₄—O, R₅—C(O)—NH—, or R₆C(O)—,wherein R₄, R₅ and R₆ are independently (C1-C7)alkyl; R₂ is(C₁-C₇)alkyl, (C₆-C₁₀)aryl-(C₁-C₇)alkyl, (5-9 membered)heteroaryl-(C₁-C₇)alkyl, or (5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.

In another embodiment, the present invention provides the compound offormula (II), wherein

R₁ is cyano, (C₁-C₇)alkyl, amino, R₄—O—, (C₁-C₇)alkyl-NHC(O)—,R₅—C(O)NH—, R₆C(O)—, R₉—C(O)—O— or R₁₀—O—(O)—, wherein

R₄, R_(6,) R_(9,) and R₁₀ are independently hydrogen, mono- ordi-(C₁-C₇)alkylamino, (C₁-C₇)alkyl or aryl each of which is optionallysubstituted by one to five substituents selected from the groupconsisting of (C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy and aryl;

R₅ is hydrogen, (C₁-C₇)alkyl or (R₇)(R₈)N—;

R₇ and R₈ are independently hydrogen, (C₁-C₇)alkyl, oraryl-(C₁-C₇)alkyl;

R₂ is hydrogen, (C₁-C₇)alkyl, which is optionally substituted by one tothree substituents selected from the group consisting of (C₁-C₇)alkyl,hydroxy, aryl, heterocyclyl, heteroaryl, (C₁-C₇)alkyl-O—C(O)—,di-(C₁-C₇)alkylamino-C(O)—, wherein each of aryl, heterocyclyl, andheteroaryl is further optionally substituted by (C₁-C₇)alkyl;

R₃ is (C₁-C₇)alkyl or cycloalkyl; or

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (II),wherein R₁ is (C₁-C₇)alkyl, R₄—O—, or R₅—C(O)NH—, wherein R₄ is(C₁-C₇)alkyl optionally substituted by one to three halo, R₅ is hydrogenor mono-(C₁-C₇)-alkylamino;

R₂ is (C₁-C₇)alkyl optionally substituted by (C₁-C₇)alkyl-O—C(O)—,di-(C₁-C₇)-alkylamino-C(O)—, hydroxy; or

R₂ is aryl-(C₁-C₇)alkyl-, heteroaryl-(C₁-C₇)alkyl-,heterocyclyl-(C₁-C₇)alkyl, wherein said heterocyclyl is optionallysubstituted by (C₁-C₇)alkyl;

R₃ is (C₁-C₇)alkyl; or

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (II),wherein

R₁ is (C₁-C₇)alkoxy;

R₂ is (C₁-C₇)alkyl;

R₃ is (C₁-C₇)alkyl.

Preferably, the present invention provides the compound of formula (II),wherein

R₁ is (C₁-C₇)alkoxy;

R₂ is (5-9 membered) heteroaryl-(C₁-C₇)alkyl;

R₃ is (C₁-C₇)alkyl.

In another aspect, the present invention provides a compound of formula(III)

Wherein

R₁ is nitro, cyano, halo, alkyl, R₄—O—, R₅—C(O)NH—, or R₆C(O)—, whereinR₄, R₅ and R₆ are independently alkyl or aryl each of which isoptionally substituted by one to five substituents selected from thegroup consisting of (C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy andaryl; and

R₂ is alkyl, aryl-alkyl-, or heteroaryl-alkyl-, heterocyclylalkyl, ormono-alkylamino-alkyl, di-alkylamino-alkyl; or

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula(III), wherein R1 is nitro, cyano, halo, (C₁-C₇)alkyl, R₄—O—,R₅—C(O)NH—, or R₆C(O)—, wherein R₄, R₅ and R₆ are independently(C₁-C₇)alkyl, phenyl, biphenyl, naphthyl, or tetrahydronaphthyl each ofwhich is optionally substituted by one to five substituents selectedfrom the group consisting of (C₁-C₇)alkyl, halo, hydroxyl and(C₁-C₇)alkoxy; R₂ is (C₁-C₇)alkyl, (C₆-C₁₀)aryl-(C₁-C₇)alkyl, or (5-9membered) heteroaryl-(C₁-C₇)alkyl, (5-9 membered)heterocyclyl-(C₁-C₇)alkyl, or mono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomers.

Also more preferably, the present invention provides the compound offormula (III), wherein R₁ is (C₁-C₇)alkyl, R₄—O, R₅—C(O)—NH—, orR₆C(O)—, wherein R₄, R₅ and R₆ are independently (C_(1-C) ₇)alkyl; R₂ is(C₁-C₇)alkyl, (5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomers.

In another embodiment, the present invention provides the compound offormula (III), wherein

R₁ is cyano, nitro, halo, alkyl, amino, R₄—O—, R₅—C(O)NH—, or R₆C(O)—,wherein R₄, R₅, and R₆ are independently alkyl or aryl each of which isoptionally substituted by one to five substituents selected from thegroup consisting of (C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy andaryl;

R₂ is alkyl, aryl-alkyl-, or heteroaryl-alkyl-, (5-9membered)heterocyclyl-(C₁-C₇)alkyl, mono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl,or di-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula(III), wherein R₁ is nitro, cyano, halo, (C₁-C₇)alkyl, R₄—, R₅—C(O)NH—,or R₆C(O)—, wherein R₄, R₅ and R₆ are independently (C₁-C₇)alkyl,phenyl, biphenyl, naphthyl, or tetrahydronaphthyl each of which isoptionally substituted by one to five substituents selected from thegroup consisting of (C₁-C₇)alkyl, halo, hydroxyl and (C₁-C₇)alkoxy; R₂is (C₁-C₇)alkyl, (C₆-C₁₀)aryl-(C₁-C₇)alkyl, or (5-9 membered)heteroaryl-(C₁-C₇)alkyl, (5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomers.

In another aspect, the present invention provides the compound offormula (IV)

Wherein

R₁ is nitro cyano, halo, alkyl, R₄—O—, R₅—C(O)NH—, or R₆C(O)—, whereinR₄, R₅ and R₆ are independently alkyl or aryl each of which isoptionally substituted by one to five substituents selected from thegroup consisting of (C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy andaryl; and

R₂ is alkyl, aryl-alkyl-, or heteroaryl-alkyl-, heterocyclylalkyl, ormono-alkylamino-alkyl, di-alkylamino-alkyl; or

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (IV),wherein R₁ is nitro, cyano, halo, (C₁-C₇)alkyl, R₄—O, R₅—C(O)NH—, orR₆C(O)—, wherein R₄, R₅ and R₆ are independently (C₁-C₇)alkyl, phenyl,biphenyl, naphthyl, or tetrahydronaphthyl each of which is optionallysubstituted by one to five substituents selected from the groupconsisting of (C₁-C₇)alkyl, halo, hydroxyl and (C₁-C₇)alkoxy; R₂ is(C₁-C₇)alkyl, (C₆-C₁₀)aryl-(C₁-C₇)alkyl, or (5-9 membered)heteroaryl-(C₁-C₇)alkyl, (5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomers.

Also more preferably, the present invention provides the compound offormula (IV), wherein R₁ is (C₁-C₇)alkyl, R₄—O, R₅—C(O)—NH—, or R₆C(O)—,wherein R₄, R₅ and R₆ are independently (C₁-C₇)alkyl; R₂ is(C₁-C₇)alkyl, (5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomers.

In another embodiment, the present invention provides the compound offormula (IV), wherein

R₁ is cyano, nitro, halo, alkyl, amino, R₄—O—, R₅—C(O)NH—, or R₆C(O)—,wherein R₄, R₅, and R₆ are independently alkyl or aryl each of which isoptionally substituted by one to five substituents selected from thegroup consisting of (C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy andaryl;

R₂ is alkyl, aryl-alkyl-, or heteroaryl-alkyl-, (5-9membered)heterocyclyl-(C₁-C₇)alkyl, mono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl,or di-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or

a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.

Preferably, the present invention provides the compound of formula (IV),wherein R₁ is nitro, cyano, halo, (C₁-C₇)alkyl, R₄—O—, R₅—C(O)NH—, orR₆C(O)—, wherein R₄, R₅ and R₆ are independently (C₁-C₇)alkyl, phenyl,biphenyl, naphthyl, or tetrahydronaphthyl each of which is optionallysubstituted by one to five substituents selected from the groupconsisting of (C₁-C₇)alkyl, halo, hydroxyl and (C₁-C₇)alkoxy; R₂ is(C₁-C₇)alkyl, (C₆-C₁₀)aryl-(C₁-C₇)alkyl, or (5-9 membered)heteroaryl-(C₁-C₇)alkyl, (5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or a pharmaceutically acceptable saltthereof; or an optical isomer thereof; or a mixture of optical isomers.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety. Preferably the alkyl comprises 1 to 20carbon atoms, more preferably 1 to 16 carbon atoms, 1 to 10 carbonatoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,n-decyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-20 carbon atoms in the ring portion. Preferably, thearyl is a (C₆-C₁₀)aryl. Non-limiting examples include phenyl, biphenyl,naphthyl or tetrahydronaphthyl, each of which may optionally besubstituted by 1-4 substituents, such as optionally substituted alkyl,trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, alkyl-C(O)—O—,aryl-O—, heteroaryl-O—, optionally substituted amino, thiol, alkylthio,arylthio, nitro, cyano, carboxy, alkyl-O—C(O)—, carbamoyl, alkylthiono,sulfonyl, sulfonamido, heterocyclyl and the like.

Furthermore, the term “aryl” as used herein, refers to an aromaticsubstituent which can be a single aromatic ring, or multiple aromaticrings that are fused together, linked covalently, or linked to a commongroup such as a methylene or ethylene moiety. The common linking groupalso can be a carbonyl as in benzophenone or oxygen as in diphenyletheror nitrogen as in diphenylamine.

As used herein, the term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—,(alkyl)₂NC(O)—, aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aryl-alkyl-NHC(O)—, alkyl(aryl-alkyl)-NC(O)—and the like.

As used herein, the term “sulfonamido” refers to alkyl-S(O)₂—NH—,aryl-S(O)₂—NH—, aryl-alkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—,heteroaryl-alkyl-S(O)₂—NH—, alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-,aryl-alkyl-S(O)₂—N(alkyl)-, heteroaryl-S(O)₂—N(alkyl)-,heteroaryl-alkyl-S(O)₂-N(alkyl)- and the like.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to anoptionally substituted, saturated or unsaturated non-aromatic ring orring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-,8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or15-membered tricyclic ring system and contains at least one heteroatomselected from O, S and N, where the N and S can also optionally beoxidized to various oxidation states. The heterocyclic group can beattached at a heteroatom or a carbon atom. The heterocyclyl can includefused or bridged rings as well as spirocyclic rings. Examples ofheterocycles include tetrahydrofuran (THF), dihydrofurari, 1,4-dioxane,morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane,imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran,dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane,oxathiane, thiomorpholine, and the like.

The term “heterocyclyl” further refers to heterocyclic groups as definedherein substituted with 1, 2 or 3 substituents selected from the groupsconsisting of the following:

(a) alkyl;

(b) hydroxy (or protected hydroxy);

(c) halo;

(d) oxo, i.e., ═O;

(e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxy;

(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic groupbonded through an oxygen bridge;

(j) alkyl-O—C(O)—;

(k) mercapto;

(l) nitro;

(m) cyano;

(n) sulfamoyl or sulfonamido;

(o) aryl;

(p) alkyl-C(O)—O—;

(q) aryl-C(O)—O—;

(r) aryl-S—;

(s) aryloxy;

(t) alkyl-S—;

(u) formyl, i.e., HC(O)—;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino,alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

As used herein, the term “sulfonyl” refers to R—SO₂—, wherein R ishydrogen, alkyl, aryl, heteroaryl, aryl-alkyl, heteroaryl-alkyl,aryl-O—, heteroaryl-O—, alkoxy, aryloxy, cycloalkyl, or heterocyclyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. As used herein, the term “lower alkoxy” refers to the alkoxygroups having about 1-7 preferably about 1-4 carbons.

As used herein, the term “acyl” refers to a group R—C(O)— of from 1 to10 carbon atoms of a straight, branched, or cyclic configuration or acombination thereof, attached to the parent structure through carbonylfunctionality. Such group may be saturated or unsaturated, and aliphaticor aromatic. Preferably, R in the acyl residue is alkyl, or alkoxy, oraryl, or heteroaryl. Also preferably, one or more carbons in the acylresidue may be replaced by nitrogen, oxygen or sulfur as long as thepoint of attachment to the parent remains at the carbonyl. Examplesinclude but are not limited to, acetyl, benzoyl, propionyl, isobutyryl,t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower acyl refers toacyl containing one to four carbons.

As used herein, the term “cycloalkyl” refers to optionally substitutedsaturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbongroups of 3-12 carbon atoms, preferably 3-7 carbon atoms, each of whichmay be substituted by one or more substituents, such as alkyl, halo,oxo, hydroxy, alkoxy, alkyl-C(O)-, acylamino, carbamoyl, alkyl-NH—,(alkyl)₂N—, thiol, alkylthio, nitro, cyano, carboxy, alkyl-O—C(O)—,sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like. Exemplarymonocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like. Exemplary bicyclic hydrocarbon groups includebornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

As used herein, the term “sulfamoyl” refers to H₂NS(O)₂—,alkyl-NHS(O)₂—, (alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—,(aryl)₂NS(O)₂—, heteroaryl-NHS(O)₂—, aralkyl-NHS(O)₂—,heteroaralkyl-NHS(O)₂— and the like.

As used herein, the term “aryloxy” refers to both an —O-aryl and an—O-heteroaryl group.

As used herein, the term acylamino refers to the group —NRC(O)R′ whereeach of R and R′ is independently hydrogen, alkyl, aryl, heteroaryl, orheterocyclyl, where both R and R′ groups are optionally joined to form aheterocyclic group (e.g., morpholino) wherein alkyl, aryl, heteroaryland heterocyclyl are as defined herein.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or fused polycyclic-ring system, having 1 to 8heteroatoms selected from N, O or S. Preferably, the heteroaryl is a5-10 membered ring system. Typical heteroaryl groups include 2- or3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-,4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl,2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl,4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, 2-, 4-, or5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring. Nonlimiting examples include but are not limited to 1-, 2-, 3-,5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-,3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-,4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinoliyl, 1-, 3-, 4-, 5-,6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-,3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-,quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-,3-, 4-, 5-, 6-, 7-, or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-,2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-,or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-,2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-,or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-,or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazol, 2-, 4-, 5-, 6-, or7-benzothiazolyl.

A heteroaryl group may be mono-, bi-, tri-, or polycyclic, preferablymono-, bi-, or tricyclic, more preferably mono- or bicyclic.

As used herein, the term “halo” or “halogen” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric formsthat may be defined, in terms of absolute stereochemistry, as (R)- or(S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the term “pharmaceutically acceptable salts” refers tosalts that retain the biological effectiveness and properties of thecompounds of this invention and, which are not biologically or otherwiseundesirable. In many cases, the compounds of the present invention arecapable of forming acid and/or base salts by virtue of the presence ofamino and/or carboxyl groups or groups similar thereto. Pharmaceuticallyacceptable acid addition salts can be formed with inorganic acids andorganic acids. Inorganic acids from which salts can be derived include,for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids from which salts canbe derived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinicacid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamicacid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceuticallyacceptable base addition salts can be formed with inorganic and organicbases. Inorganic bases from which salts can be derived include, forexample, sodium, potassium, lithium, ammonium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like; particularly preferredare the ammonium, potassium, sodium, calcium and magnesium salts.Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like, specifically such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine, andethanolamine. The pharmaceutically acceptable salts of the presentinvention can be synthesized from a parent compound, a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting free acid forms of these compounds with astoichiometric amount of the appropriate base (such as Na, Ca, Mg, or Khydroxide, carbonate, bicarbonate, or the like), or by reacting freebase forms of these compounds with a stoichiometric amount of theappropriate acid. Such reactions are typically carried out in water orin an organic solvent, or in a mixture of the two. Generally,non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are preferred, where practicable. Lists of additionalsuitable salts can be found, e.g., in Remington's PharmaceuticalSciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), whichis herein incorporated by reference.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, such like materials and combinations thereof, as would be known toone of ordinary skill in the art (see, for example, Remington'sPharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp.1289-1329, incorporated herein by reference). Except insofar as anyconventional carrier is incompatible with the active ingredient, its usein the therapeutic or pharmaceutical compositions is contemplated.

The term “therapeutically effective amount” of a compound of the presentinvention refers to an amount of the compound of the present inventionthat will elicit the biological or medical response of a subject, orameliorate symptoms, slow or delay disease progression, or prevent adisease, etc. In a preferred embodiment, the “effective amount” refersto the amount that inhibits or reduces expression or activity of MMP-9,and/or MMP-12 and/or MMP-13.

As used herein, the term “subject” refers to an animal. Preferably, theanimal is a mammal. A subject also refers to for example, primates(e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats,mice, fish, birds and the like. In a preferred embodiment, the subjectis a human.

As used herein, the term “a disorder” or “a disease” refers to anyderangement or abnormality of function; a morbid physical or mentalstate. See Dorland's Illustrated Medical Dictionary, (W.B. Saunders Co.27th ed. 1988).

As used herein, the term “inhibition” or “inhibiting” refers to thereduction or suppression of a given condition, symptom, or disease, or asignificant decrease in the baseline activity of a biological activityor process. Preferably, the condition is associated with or mediated byMMP-9, and/or MMP-12 and/or MMP-13.

As used herein, the term “treating” or “treatment” of any disease ordisorder refers in one embodiment, to ameliorating the disease ordisorder (i.e., arresting or reducing the development of the disease orat least one of the clinical symptoms thereof. In another embodiment“treating” or “treatment” refers to ameliorating at least one physicalparameter, which may not be discernible by the patient. In yet anotherembodiment, “treating” or “treatment” refers to modulating the diseaseor disorder, either physically, (e.g., stabilization of a discerniblesymptom), physiologically, (e.g., stabilization of a physicalparameter), or both. In yet another embodiment, “treating” or“treatment” refers to preventing or delaying the onset or development orprogression of the disease or disorder.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.Recitation of ranges of values herein are merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g. “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Any asymmetric carbon atom on the compounds of the present invention canbe present in the (R)-, (S)- or (R,S)-configuration, preferably in the(R)- or (S)-configuration. Substituents at atoms with unsaturated bondsmay, if possible, be present in cis-(Z)- or trans(E)-form. Therefore,the compounds of the present invention can be in the form of one of thepossible isomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound, e.g., by fractional crystallization of a saltformed with an optically active acid, Racemic products can also beresolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Finally, compounds of the present invention are either obtained in thefree form, as a salt thereof, or as prodrug derivatives thereof.

When a basic group is present in the compounds of the present invention,the compounds can be converted into acid addition salts thereof, inparticular, acid addition salts with the imidazolyl moiety of thestructure, preferably pharmaceutically acceptable salts thereof. Theseare formed, with inorganic acids or organic acids. Suitable inorganicacids include but are not limited to, hydrochloric acid, sulfuric acid,a phosphoric or hydrohalic acid. Suitable organic acids include but arenot limited to, carboxylic acids, such as (C₁-C₄)alkanecarboxylic acidswhich, for example, are unsubstituted or substituted by halogen, e.g.,acetic acid, such as saturated or unsaturated dicarboxylic acids, e.g.,oxalic, succinic, maleic or fumaric acid, such as hydroxycarboxylicacids, e.g., glycolic, lactic, malic, tartaric or citric acid, such asamino acids, e.g., aspartic or glutamic acid, organic sulfonic acids,such as (C₁-C₄)alkylsulfonic acids, e.g., methanesulfonic acid; orarylsulfonic acids which are unsubstituted or substituted, e.g., byhalogen. Preferred are salts formed with hydrochloric acid,methanesulfonic acid and maleic acid.

When an acidic group is present in the compounds of the presentinvention, the compounds can be converted into salts withpharmaceutically acceptable bases. Such salts include alkali metalsalts, like sodium, lithium and potassium salts; alkaline earth metalsalts, like calcium and magnesium salts; ammonium salts with organicbases, e.g., trimethylamine salts, diethylamine salts,tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine, lysineand the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also be used for purification of the compounds obtained.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention can also form internalsalts.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds are inactive or have low activity compared to thecorresponding active drug compound, that contains one or more protectivegroups and are converted to an active form by metabolism or solvolysis.Both the active drug form and any released metabolic products shouldhave acceptably low toxicity. Typically, the formation of active drugcompound involves a metabolic process or reaction that is one of thefollow types:

1. Oxidative reactions, such as oxidation of alcohol, carbonyl, and acidfunctions, hydroxylation of aliphatic carbons, hydroxylation ofalicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation ofcarbon-carbon double bonds, oxidation of nitrogen-containing functionalgroups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidativeN-delakylation, oxidative O- and S-delakylation, oxidative deamination,as well as other oxidative reactions.

2. Reductive reactions, such as reduction of carbonyl groups, reductionof alcoholic groups and carbon-carbon double bonds, reduction ofnitrogen-containing functions groups, and other reduction reactions.

3. Reactions without change in the state of oxidation, such ashydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogensingle bonds, hydrolytic cleavage of non-aromatic heterocycles,hydration and dehydration at multiple bonds, new atomic linkagesresulting from dehydration reactions, hydrolytic dehalogenation, removalof hydrogen halide molecule, and other such reactions.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. See, Cheng et al., US20040077595,application Ser. No. 10/656,838, incorporated herein by reference. Suchcarrier prodrugs are often advantageous for orally administered drugs.Carrier prodrugs can, for example, be used to improve one or more of thefollowing properties: increased lipophilicity, increased duration ofpharmacological effects, increased site-specificity, decreased toxicityand adverse reactions, and/or improvement in drug formulation (e.g.,stability, water solubility, suppression of an undesirable organolepticor physiochemical property). For example, lipophilicity can be increasedby esterification of hydroxyl groups with lipophilic carboxylic acids,or of carboxylic acid groups with alcohols, e.g., aliphatic alcohols.Wermuth, The Practice of Medicinal Chemistry, Ch. 31-32, Ed. Werriuth,Academic Press, San Diego, Calif., 2001.

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acyland O-acyl derivatives of thiols, alcohols or phenols, wherein acyl hasa meaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid, e.g., lower alkyl esters,cycloalkyl esters, lower alkenyl esters, benzyl esters, mono- ordi-substituted lower alkyl esters, such as the ω-(amino, mono- ordi-lower alkylamino, carboxy, lower alkoxycarbonyl)-lower alkyl esters,the α-(lower alkanoyloxy, lower alkoxycarbonyl or di-loweralkylaminocarbonyl)-lower alkyl esters, such as the pivaloyloxymethylester and the like conventionally used in the art. In addition, amineshave been masked as arylcarbonyloxymethyl substituted derivatives whichare cleaved by esterases in vivo releasing the free drug andformaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)). Moreover, drugscontaining an acidic NH group, such as imidazole, imide, indole and thelike, have been masked with N-acyloxymethyl groups (Bundgaard, Design ofProdrugs, Elsevier (1985)). Hydroxy groups have been masked as estersand ethers. EP 039,051 (Sloan and Little) discloses Mannich-basehydroxamic acid prodrugs, their preparation and use.

In view of the close relationship between the compounds, the compoundsin the form of their salts and the pro-drugs, any reference to thecompounds of the present invention is to be understood as referring alsoto the corresponding pro-drugs of the compounds of the presentinvention, as appropriate and expedient.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization.

The compounds of the present invention have valuable pharmacologicalproperties, they are useful as inhibitors of matrix metalloproteinasessuch as matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 12(MMP-12) and matrix metalloproteinase 13 (MMP-13). MMP-9 also known asgelatinase B acts mainly in the remodeling of extracellular matrix andhas been indicated in tumors, autoimmune diseases, chronical obstructivepulmonary disease (COPD), coronary artery diseases and neurodegenerativediseases, etc. See Van den Steen, P et al., Critical Reviews inBiochemistry and Molecular Biology, 37(6):375-536 (2002). MMP12, alsoknown as macrophage elastase or metalloelastase, is able to degradeextracellular matrix components such as elastin and is involved intissue remodeling processes. MMP-12 has been indicated to be a keyprotein in the pathologenesis of tumor invasiveness, arthritis,atherosclerosis, Alport syndrome, and chronical obstructive pulmonarydisease (COPD). MMP-13 also known as collagenase 3, has been indicated(1) in extracellular matrix degradation and cell-matrix interactionassociated with metastasis especially as observed in invasive breastcancer lesions and in malignant epithelia growth in skin carcinogenesis;and (2) during primary ossification and skeletal remodelling (M.Stahle-Backdahl et al., (1997) Lab. Invest. 76 (5):717-728; N. Johanssonet al., (1997) Dev. Dyn. 208(3):387-397), in destructive joint diseasessuch as rheumatoid and osteo-arthritis (D. Wernicke et al., (1996) J.Rheumatol. 23:590-595; P. G. Mitchell et al., (1996) J. Clin. Invest.97(3):761-768; O. Lindy et al., (1997) Arthritis Rheum 40(8:1391-1399);and the aseptic loosening of hip replacements (S. Imai et al., (1998) J.Bone Joint Surg. Br. 80(4):701-710). MMP13 has also been implicated inchronic adult periodontitis as it has been localized to the epitheliumof chronically inflamed mucosa human gingival tissue (V. J. Uitto etal., (1998) Am. J. Pathol 152(6):1489-1499) and in remodelling of thecollagenous matrix in chronic wounds (M. Vaalamo et al., (1997) J.Invest. Dermatol. 109(1): 96-101).

Accordingly, the compounds of the present invention are also useful fortreatment of a disorder or a disease mediated by MMP-9, and/or MMP-12,and/or MMP-13. In particular, the compounds of the present invention areuseful for treatment of at least one disorder or disease selected fromAlport syndrome, asthma, rhinitis, chronic obstructive pulmonarydiseases (COPD), arthritis (such as rheumatoid arthritis andosteoarthritis), atherosclerosis and restenosis, cancer invasion andmetastasis, diseases involving tissue destruction, loosening of hipjoint replacements, periodontal disease, fibrotic disease, infarctionand heart disease, liver and renal fibrosis, endometriosis, diseasesrelated to the weakening of the extracellular matrix, heart failure,aortic aneurysms, CNS related diseases such as Alzheimer's disease andMultiple Sclerosis (MS), hematological disorders.

Additionally, the present invention provides:

a compound of the present invention for use as a medicament;

the use of a compound of the present invention for the preparation of apharmaceutical composition for the delay of progression and/or treatmentof a disorder or disease mediated by MMP-9, and/or MMP-12, and/orMMP-13.

the use of a compound of the present invention for the preparation of apharmaceutical composition for the delay of progression and/or treatmentof a disorder or disease mediated by MMP-9, and/or MMP-12, and/orMMP-13.

the use of a compound of the present invention for the preparation of apharmaceutical composition for the delay of progression and/or treatmentof a disorder or disease selected from Alport syndrome, asthma,rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis (suchas rheumatoid arthritis and osteoarthritis), atherosclerosis andrestenosis, cancer invasion and metastasis, diseases involving tissuedestruction, loosening of hip joint replacements, periodontal disease,fibrotic disease, infarction and heart disease, liver and renalfibrosis, endometriosis, diseases related to the weakening of theextracellular matrix, heart failure, aortic aneurysms, CNS relateddiseases such as Alzheimer's disease and Multiple Sclerosis (MS),hematological disorders.

The compounds of formula (I)-(IV) can be prepared by the proceduresdescribed in the following sections.

Generally, the compounds of formula (I) and (III) can be preparedaccording to Scheme 1, which contains six steps.

As to the individual steps in the above scheme, step 1 involves thesulfonylation of a amino acid (formula (V)) with a 3-R₁-benzene sulfonylchloride (formula (VI)) to yield an N-aryl sulfonamide substituted aminoacid. Step 2 involves protection of the acid functionality as the benzylester, which allows for regioselective N alkylation of the sulfonamidenitrogen in step 3. Following the alkylation, the benzyl protectinggroup is removed via hydrogenolysis and the acid is converted to thehydroxamic acid in a two step procedure using the trityl protectedhydroxylamine followed by removal of the trityl protecting group in thelast step.

Alternatively, different alkoxy-substituted compounds of formula (I) canbe prepared from the benzyl protected intermediate described above(Scheme 1, where X is an acetoxy group), according to Scheme 2, whichcontains 2 steps. The conversion of the benzyl ester intermediate to thehydroxamic acid is accomplished in the same manner described in Scheme 1

As to the individual steps in Scheme 2, step 1 involves the hydrolysisof the ester to provide the phenolic intermediate, step 2 involves thealkylation of the phenol to give the requisite ether or carbamate, asdefined above.

Alternatively, different acylamino-substituted compounds of formula (I)can be prepared from the benzyl protected intermediate described aboveScheme 1, where X is a nitro group), according to Scheme 3, whichcontains 2 steps. The conversion of the benzyl ester intermediate to thehydroxamic acids of Formula (I) is accomplished in the same mannerdescribed in Scheme 1

As to the individual steps in Scheme 3, step 1 involves the reduction ofthe nitro group to the aniline intermediate. Step 2 involves theacylation of the aniline to give the requisite urea or acylamino groupas defined above.

Additional compounds of the formula (I) can be prepared in an alternatemanner as seen in Scheme 4.

More specifically, the analogs in scheme 4 can be synthesized through aseries of chemical transformations starting with the allyl-amineintermediate, which can be prepared in a manner analogous to thealkylation illustrated in scheme 1. Hydroboration of this intermediate,followed by mesylation and subsequent displacement leads to theincorporation of the R6 moiety. In a similar manner to scheme 1, thebenzyl ester intermediate is converted to the hydroxamic acids ofFormula (I).

Compounds of Formula (I), where R2 is equal to hydroxyethyl, can besynthesized in an alternate fashion to those described above.

The starting material for the synthesis of the hydroxyethyl analogs issynthesized as described for scheme 1. Alkylation of this intermediate,followed by cyclization affords the lactone intermediate, which issubsequently opened under Weinreb conditions. Deprotection of the benzylgroup is accomplished under standard hydrogenation conditions.

Generally, the compounds of formula (II) and (IV) can be prepared bymethods of preparing enantiomers of the compounds known to those skilledin the art by resolving racemic mixtures, such as by formation andrecrystallization of diastereomeric salts or by chiral chromatography orHPLC separation utilizing chiral stationery phases.

Preferably, the compounds of formula (II) and (IV) can be preparedstarting with materials in the form of the intended enantiomer and usingthe schemes described herein, such that the resulting final compoundsare in the form of the intended enantiomer.

In starting compounds and intermediates which are converted to thecompounds of the present invention in a manner described herein,functional groups present, such as amino, thiol, carboxyl and hydroxygroups, are optionally protected by conventional protecting groups thatare common in preparative organic chemistry. Protected amino, thiol,carboxyl and hydroxyl groups are those that can be converted under mildconditions into free amino thiol, carboxyl and hydroxyl groups withoutthe molecular framework being destroyed or other undesired sidereactions taking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, carboxy, etc.), the structure and stability of the moleculeof which the substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, NY (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, room temperature or elevated temperatures, preferably ator near the boiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form including capsules, tablets,pills, granules, powders or suppositories, or in a liquid form includingsolutions, suspensions or emulsions. The pharmaceutical compositions canbe subjected to conventional pharmaceutical operations such assterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers etc.

Preferably, the pharmaceutical compositions are tablets and gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient in admixture withnontoxic pharmaceutically acceptable excipients which are suitable forthe manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, preferably about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with carrier. Advantageouscarriers include absorbable pharmacologically acceptable solvents toassist passage through the skin of the host. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound of the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The pharmaceutical compositions contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include 1) AT₁ receptor antagonists selected from the groupconsisting of abitesartan, benzyllosartan, candesartan, elisartan,embusartan, enoltasosartan, eprosartan, fonsartan, forasartan,glycyllosartan, irbesartan, isoteoline, losartan, milfasartan,olmesartan, opomisartan, pratosartan, ripisartan, saprisartan,saralasin, sarmesin, tasosartan, telmisartan, valsartan, zolasartan;Kissei KRH-94, Lusofarmaco LR-B/057, Lusofarmaco LR-B/081, LusofarmacoLR B/087, Searle SC-52458, Sankyo CS-866, Takeda TAK-536, UriachUR-7247, A-81282, A-81988, BIBR-363, BIBS39, BIBS-222, BMS-180560,BMS-184698, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996,CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, GA-0056, E-4177,EMD-66397, EMD-73495, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803,EXP-7711, EXP-9270, FK-739, HN-65021, HR-720, ICI-D6888, ICI-D7155,ICI-D8731, KR1-1177, KT3-671, KW-3433, L-158809, L-158978, L-159282,L-159689, L-159874, L-161177, L-162154, L-162234, L-162441, L-163007,L-163017, LY-235656, LY-285434, LY-301875, LY-302289, LY-315995,ME-3221, PD-123177, PD-123319, PD-150304, RG-13647, RWJ-38970,RWJ-46458, S-8307, S-8308, SL-91.0102, U-96849, U-97018, UP-269-6,UP-275-22, WAY-126227, WK-1492.2K, WK-1360, X-6803, XH-148, XR-510,YM-358, YM-31472, ZD-6888, ZD-7155 and ZD-8731 which are all known perse, or any physiologically compatible salts, solvates, prodrugs oresters thereof; 2) non-selective alpha-adrenoceptor antagonists, e.g.tolazoline or phenoxybenzamine; 3) selective alpha-adrenoceptorantagonists, e.g. doxazosin, prazosin, terazosin or urapidil;beta-adrenoceptor antagonists, e.g. acebutolol, alprenolol, atenolol,betaxolol, bisoprolol, bupranolol, carazolol, carteolol, celiprolol,mepindolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol,pindolol, propranolol, sotalol and timolol; 4) mixed antagonists ofalpha- and beta-adrenoceptors, e.g. carvedilol or labetolol; ganglionblockers, e.g. reserpine or guanethidine; 5) alpha2-adrenoceptoragonists (including centrally acting alpha2-adrenoceptor agonists), e.g.clonidine, guanfacine, guanabenz methyldopa and moxonidine; 6) rennininhibitors, e.g. alskiren; 7) ACE inhibitors, e.g. benazepril,captopril, cilazapril, enalapril, fosinopril, imidapril, lisinopril,moexipril, quinapril, perindopril, ramipril, spirapril or trandolapril;8) mixed or selective endothelin receptor antagonists e.g. atrasentan,bosentan, clazosentan, darusentan, sitaxsentan, tezosentan, BMS-193884or J-104132; direct vasodilators, e.g. diazoxide, dihydralazine,hydralazine or minoxidil; 9) mixed ACE/NEP dual inhibitors, e.g.omapatrilat; ECE inhibitors, e.g. FR-901533; PD-069185; CGS-26303;CGS-34043; CGS-35066; CGS-30084; CGS-35066; SM-19712; Ro0677447; 10)selective NEP inhibitors; 11) vasopressin antagonists; 12) aldosteronereceptor antagonists, e.g. eplerenone; 13) aldosterone inhibitors; 14)angiotensin vaccine; and 15) urotensin II receptor antagonists.

Furthermore, the combinations as described above can be administered toa subject via simultaneous, separate or sequential administration (use).Simultaneous administration (use) can take place in the form of onefixed combination with two or more active ingredients, or bysimultaneously administering two or more compounds that are formulatedindependently. Sequential administration (use) preferably meansadministration of one (or more) compounds or active ingredients of acombination at one time point, other compounds or active ingredients ata different time point, that is, in a chronically staggered manner,preferably such that the combination shows more efficiency than thesingle compounds administered independently (especially showingsynergism). Separate administration (use) preferably meansadministration of the compounds or active ingredients of the combinationindependently of each other at different time points, preferably meaningthat two compounds are administered such that no overlap of measurableblood levels of both compounds are present in an overlapping manner (atthe same time).

Also combinations of two or more of sequential, separate andsimultaneous administrations are possible, preferably such that thecombination compound-drugs show a joint therapeutic effect that exceedsthe effect found when the combination compound-drugs are usedindependently at time intervals so large that no mutual effect on theirtherapeutic efficiency can be found, a synergistic effect beingespecially preferred.

Additionally, the present invention provides:

a pharmaceutical composition or combination of the present invention foruse as a medicament;

the use of a pharmaceutical composition or combination of the presentinvention for the delay of progression and/or treatment of a disorder ordisease mediated by MMP-9, and/or MMP-12 and/or MMP-13.

the use of a pharmaceutical composition or combination of the presentinvention for the delay of progression and/or treatment of a disorder ordisease selected from hypokalemia, hypertension, congestive heartfailure, renal failure, in particular, chronic renal failure,restenosis, atherosclerosis, syndrome X, obesity, nephropathy,post-myocardial infarction, coronary heart diseases, increased formationof collagen, fibrosis and remodeling following hypertension andendothelial dysfunction.

the use of a pharmaceutical composition or combination of the presentinvention for the delay of progression and/or treatment of a disorder ordisease selected from gynecomastia, osteoporosis, prostate cancer,endometriosis, uterine fibroids, dysfunctional uterine bleeding,endometrial hyperplasia, polycystic ovarian disease, infertility,fibrocystic breast disease, breast cancer and fibrocystic mastopathy.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredients for asubject of about 50-70 kg, preferably about 5-500 mg of activeingredients. The therapeutically effective dosage of a compound, thepharmaceutical composition, or the combinations thereof, is dependent onthe species of the subject, the body weight, age and individualcondition, the disorder or disease or the severity thereof beingtreated. A physician, clinician or veterinarian of ordinary skill canreadily determine the effective amount of each of the active ingredientsnecessary to prevent, treat or inhibit the progress of the disorder ordisease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., preferably aqueous solutions, and in vivo either enterally,parenterally, advantageously intravenously, e.g., as a suspension or inaqueous solution. The dosage in vitro may range between about 10⁻³ molarand 10⁻⁹ molar concentrations. A therapeutically effective amount invivo may range depending on the route of administration, between about0.1-500 mg/kg, preferably between about 1-100 mg/kg.

The activities of a compound according to the present invention can beassessed by the following methods well-described in the art.Determination of IC₅₀ values in MMP assays Dose-response curves areprepared in DMSO/water solution (90/10, v/v) in 96-well plate format andstored at 4° C. up to 24 hours prior to analysis. In all stepspoly-propylene pipette tips are changed avoiding cross-contamination orcompound carry over. On the day of the assay, each compound is furtherdiluted (1/33.33; 96-well plate format) in water containing 0.05% CHAPSto 3-times the desired assay concentration. In the assay for eachcompound, 11 concentrations ranging from 30 to 0.0003 μM areinvestigated (0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, 10, 30μM). A three-fold concentrated MMP solution is prepared in two-foldconcentrated assay buffer 100 mM Tris-HCl buffer, pH 7.5 containing 100mM NaCl, 10 mM CaCl₂, 10 μM ZnCl₂, 0.05% Brij-35 and dispensed in96-well Greiner plates. Similarly a three-fold concentrated substratesolution (15 μM) is prepared in 100 mM Tris-HCl buffer, pH 7.5containing 100 mM NaCl, 10 mM CaCl₂, 10 μM ZnCl₂, 0.05% Brij-35 anddispensed in 96-well Greiner plates. Transfer of compounds, substrateand enzyme from 96-well plates to 384-well plates is made using eitherCybi™well or Cybi™disk devices.

The assay procedure is the following, in each well, 10 μL water/CHAPS(±test compound) is added, followed by 10 μL human MMP solution (finalassay concentration 0.5 nM). After 1 hour of incubation at roomtemperature the assay is started by addition of 10 μL substrate solution(final concentration 5 μM).

The reaction is allowed to proceed for 1 hours at ambient temperature(˜20-22° C.). At the end of the incubation the fluorescence is measuredas described above.

The apparent inhibition constant, IC₅₀, is determined from the plot ofpercentage of inhibition vs. inhibitor concentration using non-linearregression analysis software (XLfit, Vers. 3.0.5; ID Business SolutionLtd., Guildford, Surrey, UK).

In vivo models which are useful for the study of MMP inhibitors havebeen reported in the literature. Some of these can be found in thefollowing references: “Role of MMP-9 and MMP-12 in Atherosclerosis”Luttun et al in Circulation. 2004;109:1408-1; “MacrophageMetalloelastase as a Major Factor for Glomerular Injury inAnti-Glomerular Basement Membrane Nephritis” Kaneko et. al The Journalof Immunology, 2003, 170: 3377-3385; “MMP-12 has a role in abdominalaortic aneurysms in mice” Longo et al Surgery 2005;137:457-62;“Expression and Localization of Macrophage Elastase (MatrixMetalloproteinase-12) in Abdominal Aortic Aneurysms” Curci et. al J.Clin. Invest. 1998. 102:1900-D1910.

MMP02 MMP13 MMP12 MMP09 # Compound IC50 (μM) IC50 (μM) IC50 (μM) IC50(μM) 2-4

1.7 0.095 0.0175 0.725 2-6

11.1 0.25 0.0175 1.5 2-7

13.95 0.5 0.225 7.825 2-13

10.25 1.15 0.035 17.35 2-17

28.256 2.4382 0.226275 12.49255 2-23

12.5 0.8 0.145 3.5 2-26

8.75 0.85 0.055 3.7 2-27

40.25 4.95 0.3 22.7 2-28

3.15 1.55 0.05 3.1 2-34

3.7 1.2 0.065 6.9 2-38

>30 25.45 0.65 >30 2-39

>30 6.55 0.4 >30 4-4

1.35 0.05 0.0015 0.9 5

7.7 0.07 0.0055 0.4 6

3 0.03 0.002 0.3

Abbreviations:

-   DMSO: Dimethyl sulfoxide-   CHAPS: 3-[(3-Cholamidopropyl)dimethylammonio]-1-propanesulfonate-   DMF: Dimethyl Formamide-   Hex-EtOAc: Hexanes/Ethyl Acetate-   DCM: Dichloromethane-   HOAT: 1-Hydroxy-7-azabenzotriazole-   EDCI: N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide-   HCl: Hydrochloric acid-   MgSO₄: Magnesium sulfate-   K₂CO₃: Potassium carbonate-   MeOH: Methanol-   DIAD: Diisopropyl azodicarboxylate-   THF: Tetrahydrofuran-   DMS: Dimethylsulfide-   DIPEA: Diisopropylethylamine-   DIC: N,N′-Diisopropylcarbodiimide-   DMAP: 4-Di(methylamino)pyridine-   9-BBN: 9-Borabicyclo[3.3.1]nonane-   Pd(PPh₃)₄: Tetrakis(triphenylphosphine)palladium(0)-   rt: Room temperature

EXAMPLES

The present invention will now be illustrated by reference to thefollowing examples which set forth particularly advantageousembodiments. However, it should be noted that these embodiments areillustrative and are not to be construed as restricting the invention inany way. The compounds in the following examples have been found to haveIC50 values for MMP-9, MMP-12 and MMP-13 in the range of about 0.1 nM toabout 10 μM.

Example 1 N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucine hydroxamicacid

This compound is prepared in 6 steps according to the sequenceillustrated above in Scheme 1 as follows:

Step 1: N-(3 Methoxyphenylsulfonyl)D-tert-leucine

D-tert-leucine (3 g, 22.9 mmol), 3-methoxy benzenesulfonyl chloride(4.68 g, 22.6 mmol) and triethylamine (6.4 ml, 45.7 mmol) are stirred indioxane-water (1:1, 60 ml) at ambient temperature for 20 minutes. Thereaction mixture is concentrated in vacuo and the residue isre-dissolved in Ethyl Acetate and washed with 1 N HCl. The organics areseparated and washed with brine. The organic layer is dried over MgSO₄and concentrated to afford the title compound as a white solid (6.36 g,92% yield). ¹H-NMR (CDCl₃, 400MHz): δ 7.49 (d, 1H, J=8), 7.39 (s, 1H),7.32 (t, 1H, J=8.11), 7.00 (m, 1H), 5.67 (d, 1H, J=12), 3.86 (s, 3H),3.42 (d, 2H, J=8), 1.01 (s, 9H). Mass spectrum (302.0; M+1, 300.0; M−1).

Step 2: N-(3 Methoxyphenylsulfonyl)D-tert-leucine benzyl ester

N-(3 Methoxyphenylsulfonyl)D-tert-leucine (3.03 g, 10.1 mmol) isdissolved in DMF (30 ml). Potassium Carbonate (2.81 g, 20.1 mmol) isadded followed by Benzyl Bromide (1.21 ml, 9.95 mmol) and the reactionis stirred at ambient temperature for 18 hours. The reaction mixture ispartitioned between Ethyl Acetate and 1 N HCl. The organics areseparated and washed with brine, dried over MgSO₄ and concentrated. Theresidue is purified by column chromatography eluting with a gradient of5-60% (Hex-EtOAc) to give the title compound (3.08 g, 78% yield). Massspectrum (392.2; M+1, 390.2; M−1).

Step 3: N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucine benzyl ester

To a solution of N-(3 Methoxyphenylsulfonyl)D-tert-leucine benzyl ester(1.31 g, 3.35 mmol) in DMF (10 ml) is added K₂CO₃ (1.87 g, 13.4 mmol)followed by 1-iodo-3-methyl butane (1.33 g, 6.69 mmol) and the reactionmixture is heated to 70° C. overnight. The reaction is cooled to roomtemperature and then poured over 1 N HCl and extracted with EthylAcetate. The organics are washed with brine, dried over MgSO₄ andconcentrated. The crude product is purified by column chromatographyeluting with a gradient of 5-40% (Hex-EtOAc) affording the titlecompound as a colorless oil (1.0 g, 65% yield). Mass spectrum (462.3;M+1).

Step 4: N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucine

To a solution of N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucinebenzyl ester (2.0 g, 4.33 mmol) in MeOH (12 ml) is added 10% palladiumon carbon (200 mg) and the reaction is stirred under ambient pressure ofhydrogen for 4 hours. The reaction is filtered through celite andconcentrated affording the title compound (1.6 g, 99%).

H-NMR (CDCl₃, 400 MHz): δ 7.35 (d, 1H, J=8), 7.31-7.26 (m, 2H), 6.99 (m,1H), 4.26 (s, 1H), 3.77 (s, 3H), 3.39-3.32 (m, 1H), 3.21-3.13 (m, 1H),1.88-1.85 (m, 1H), 1.54-1.53 (m, 2H) 1.03 (s, 9H), 0.88-0.78 (m, 6H).Mass spectrum (372.2; M+1, 370.2; M−1).

Step 5: N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucine O-tritylhydroxamic acid

To a solution of N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucine(2.0 g, 5.38 mmol) in DCM (50 ml) is added HOAT (1.45 g, 10.8 mmol),EDCI (2.12 g, 10.8 mmol), O-trityl hydroxylamine (2.96 g, 10.8 mmol) andtriethylamine (1.51 ml, 10.8 mmol) and the reaction mixture is stirredat ambient temperature for 18 hours. The reaction is quenched with 1 NHCl and extracted with dichloromethane. The combined organic layers arewashed with brine and concentrated. The crude product is purified bycolumn chromatography eluting with a gradient of 5-40% (Hex-EtOAc)affording the title compound (2.8 g, 83%). H-NMR (CDCl₃, 400 MHz): δ7.46-7.44 (m, 9H), 7.37-7.18 (m, 10H), 7.03 (m, 1H), 4.95 (s, 1H), 3.87(s, 3H), 3.57-3.53 (m, 1H), 3.44-3.38 (m, 2H), 1.93-1.88 (m, 1H),1.55-1.45 (m, 2H), 0.95-0.87 (m, 6H), 0.73 (s, 9H). Mass spectrum(627.4; M−1).

Step 6: N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucine hydroxamicacid

To a solution of N-isoamyl-N-(3 Methoxyphenylsulfonyl)D-tert-leucineO-trityl hydroxamic acid (2.8 g, 4.45 mmol) in DCM (25 ml) is addedtrifluoroacetic acid (2.76 ml, 35.6 mmol) followed by triethyl silane(1.45 g, 8.9 mmol) and the reaction is allowed to stir at ambienttemperature for 10 minutes. The reaction is diluted with DCM, washedwith water and brine, dried over MgSO₄ and concentrated by half. Theprecipitated product is collected by filtration, washed with hexanes anddried in vacuo affording the title compound as a white solid (0.82 g,48%). H-NMR (MeOD, 400 MHz): δ 7.44 (m, 2H), 7.38 (s, 1H), 7.17 (m, 1H),4.03 (m, 2H), 3.87 (s, 3H), 3.18 (m, 1H), 1.85 (m, 1H), 1.52-1.41 (m,2H), 1.12 (s, 9H), 0.95 (s, 6H). MP 115.5-116.5. Mass spectrum (387.1;M+1, 385.2; M−1). CHN CalcCHN 55.94, 7.82, 7.25 Found CHN 55.84, 8.01,7.10.

Example 2

The following compounds are prepared analogously to Example 1 startingfrom the requisite amino acid ester derivative.

Example R1 R2 R3 e/z 2-1 MeO H t-butyl M + H: 317.1 2-2 Me Isopentylt-butyl M − H: 369.2 2-3 MeO n-Propyl t-butyl M − H: 357.1 2-4 ClIsopentyl t-butyl M − H: 389.2 2-5 F Isopentyl t-butyl M − H: 373.3 2-6MeO Isobutyl t-butyl M − H: 371.5 2-7 Et Isopentyl t-butyl M − H: 383.52-8 CF₃O Isopentyl t-butyl M − H: 439.4 2-9 Br Isopentyl t-butyl M − H:433.2, 435.2 2-10 MeO Methyl t-butyl M + H: 331.0 2-11 MeO Ethyl t-butylM − H: 343 2-12 CH₃C(O)— Isopentyl t-butyl M + H: 399.2 2-13 CH3(CO)NH—Isopentyl t-butyl M + H: 414.3 2-14 Me Isopentyl Isopropyl M + H: 357.12-15 Cyano Isopentyl Isopropyl M − H: 366.1 2-16 MeO Isopentyl IsopropylM + H: 373.3 2-17 EtO Isopentyl Isopropyl M + H: 387.4 2-18 i-BuOisopentyl isopropyl M + H: 415.4 2-19 Et(CO)NH— isopentyl t-butyl M + H:428.3 2-20 iPr-(CO)NH— Isopentyl t-butyl M + H: 442.3 2-21 EtNH(CO)NH—isopentyl t-butyl M + H: 443.3 2-22 EtO—(CO)—NH— isopentyl t-butyl M +H: 444.3 2-23 MeO Benzyl t-butyl M + H: 407.2 2-24 Et n-Propyl t-butylM + H: 357.2 2-25 Et Isobutyl t-butyl M + H: 371.2 2-26 MeO MeO(CO)CH2—t-butyl M + H: 390.1 2-27 MeO Me2N(CO)CH2— t-butyl M + H: 402.3 2-28 NH2Isoamyl t-butyl M + H: 372.3 2-29 Et(CO)NH— Isoamyl t-butyl M + H: 428.32-30 H(CO)NH— Isoamyl t-butyl M + H: 400.3 2-31 nPr(CO)NH— Isoamylt-butyl M + H: 442.5 2-32 MeNH(CO)NH— Isoamyl t-butyl M + H: 429.4 2-33nPrNH(CO)NH— Isoamyl t-butyl M + H: 457.4 2-34 iPrNH(CO)NH— Isoamylt-butyl M + H: 457.4 2-35 BnNH(CO)NH— Isoamyl t-butyl M + H: 505.5 2-36EtNH(CO)O— Isoamyl t-butyl M + H: 444.2 2-37 EtNH(CO)— n-Propyl t-butylM + H: 400.5 2-38 MeNH(CO)— n-Propyl t-butyl M + H: 386.4 2-39 MeO(CO)—n-Propyl t-butyl M − H: 385.3 2-40 HO(CO)— n-Propyl t-butyl M − H: 371.32-41 EtNH(CO)NH— n-Propyl t-butyl M + H: 415.5 2-42 MeO 3-picolylIsopropyl M + H: 379.1 2-43 MeO 3-picolyl t-butyl M + H: 408.1Alternate to Step 3 (for picolyl analogs 2-42 and 2-43):

To a solution of N-(3 Methoxyphenylsulfonyl)D-tert-leucine benzyl ester(500 mg, 1.33 mmol) in THF (7 mL) cooled to 0° C. is addedtriphenylphospine (427.5 mg, 1.46 mmol), 3-pyridylcarbinol (0.142 mL,1.46 mmol), and DIAD (0.287 mL, 1.46 mmol). The reaction is warmed toroom temperature and stirred overnight. The reaction is diluted withethyl acetate, washed with brine, and the organic layer is dried withsodium sulfate and concentrated. The crude product is purified usingcolumn chromatography eluting with a gradient of 25-100% ethyl acetatein heptane containing 1% triethylamine to afford the product as a clearoil (623 mg, 100%). Mass spectrum (469.1; M+1).

Example 3N²-[3-(Dimethylamino)propyl]-N-hydroxy-N²-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinamide

This compound is prepared according to the sequence illustrated above inScheme 4 as follows:

Step 1: BenzylN-(3-hydroxypropyl)-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate

To a solution of benzylN-allyl-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate (12.7 g, 29.3mmol) in THF (90 mL) cooled to 0° C., borane-DMS complex (5M in diethylether, 12 mL, 60.0 mmol) is added dropwise. The reaction mixture isslowly warmed up to rt and is allowed to stir at rt for 24 h. To thereaction mixture, sodium perborate tetrahydrate (27.1 g, 176 mmol) andde-ionized water (90 mL) are added in portions. The reaction mixture isstirred for additional 3 h. The reaction mixture is filtered to removethe white precipitates, then the aqueous layer is extracted with EtOAc.The organic extracts are combined, washed with brine, dried over sodiumsulfate, and concentrated in vacuo to obtain a highly viscous yellowoil. The crude product is purified by column chromatography eluting witha gradient of 25-65% EtOAc/heptane to obtain the desired alcohol as acolorless oil (9.08 g). Mass spectrum (450.46; M+1).

Step 2: BenzylN-[(3-methoxyphenyl)sulfonyl]-3-methyl-N-{3-[(methylsulfonyl)oxy]propyl}-D-valinate

To a solution of benzylN-(3-hydroxypropyl)-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate(9.08 g, 20.2 mmol) and triethylamine (4.2 mL, 30.3 mmol) in DCM (15 mL)cooled to −78° C., methanesulfonyl chloride (1.9 mL, 24.2 mmol) is addeddropwise, and the reaction mixture is allowed to stir at −78° C. for 20min. The reaction mixture is warmed up to rt, washed with de-ionizedwater, then concentrated in vacuo. The crude product is purified bycolumn chromatography eluting with a gradient of 25-100% EtOAc/heptaneto obtain the desired mesylate (9.45 g, 89% yield). Mass spectrum(528.46; M+1).

Step 3: BenzylN-[3-(dimethylamino)propyl]-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate

To a solution of benzylN-[(3-methoxyphenyl)sulfonyl]-3-methyl-N-{3-[(methylsulfonyl)oxy]propyl}-D-valinate(2.00 g, 3.79 mmol) in DCM (15 mL), dimethylamine in THF (2M, 9.5 mmol,19.0 mmol) and DIPEA (1.99 mL, 11.4 mmol) are added, and the reactionmixture is allowed to stir at rt for 18 h. Additional 3.0 mL ofdimethylamine in THF (2M) is added to the reaction mixture and isallowed to stir for additional 3 d. The reaction was approximately 50%complete. The reaction mixture is concentrated in vacuo and is purifiedby silica gel chromatography eluting with a gradient of 5-100%EtOAc/heptane to obtain the desired intermediate (500 mg, 28% yield).Mass spectrum (477.5; M+1).

Step 4:N²-[3-(Dimethylamino)propyl]-N-hydroxy-N²-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinamide

To a de-gassed solution of benzylN-[3-(dimethylamino)propyl]-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate(500 mg, 0.634 mmol) in methanol (10 mL), catalytic palladium on carbon(10% on activated carbon, 7 mg, 0.063 mmol) is added and the reactionmixture is stirred vigorously under hydrogen for 78 h. The reactionmixture is diluted with anhydrous DMF (5 mL), concentrated in vacuo toremove methanol. To the DMF solution of the acid intermediate,O-(tetrahydro-2H-pyranyl)hydroxylamine (149 mg, 1.27 mmol), EDC.HCl (249mg, 1.27 mmol), and HOAt (173 mg, 1.27 mmol) are added at rt. Thereaction was allowed to stir at rt for 18 h and was complete by LC/MS.To the reaction mixture, sodium bicarbonate decahydrate (779 mg, 2.64mmol) is added and is stirred vigorously for 30 min. The decahydratecrystals are filtered, and the filterate is concentrated in vacuo, andpurified by silica gel chromatography eluting with 15-100%EtOAc/heptanes to obtain 250 mg of the THP-protected hydroxamideintermediate. (81% yield over 2 steps). To the solution of theintermediate in methanol (1 mL), concentrated hydrochloric acid solution(37% in water, 840 mL, 0.70 mmol) is added dropwise. The reactionmixture is stirred for 15 min, resulting in the precipitation ofslightly pink white solid. The precipitate is washed with methanol andether, then dried in vacuo to give the desired product as a white solid(227 mg, 100% yield). ¹H NMR (400 MHz, d₆-DMSO) δ ppm 10.82 (s, 1H),9.86 (brs, 1H), 8.91 (s, 1H), 7.52-7.90 (m, 2H), 7.35 (m, 1H), 7.24 (m,2H), 3.98 (m, 1H), 3.97 (s, 1H), 3.85 (s, 3H), 3.07 (ddd, J=12, 4, 4 Hz,1H), 2.97 (m, 2H), 2.73 (brs, 6H), 2.13 (m, 1H), 1.94 (m, 1H), 1.01 (s,9H). Mass spectrum (402.20; M+1).

Example 4

The following compounds are prepared analogously to Example 3 startingfrom the requisite amino acid ester derivative.

Example R1 R6 e/z 4-1 MeO

M + H: 442.2 4-2 MeO

M + H: 444.2 4-3 MeO

M + H: 457.3 4-4 EtNH(CO)NH—

M + H: 498.2 4-5 EtNH(CO)NH—

M + H: 500.5

Example 5

The following compound is prepared analogously to example 4, howeverincorporation of the pyridine moiety is accomplished through a Suzukicoupling.

(R)-2-[(3-Methoxy-benzenesulfonyl)-(3-pyridin-3-yl-propyl)-amino]-3,3-dimethyl-butyricacid benzyl ester

To a solution of benzylN-allyl-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate (222.6 mg, 0.5mmol) in THF (1 mL) cooled to 0° C. is slowly added a 0.5M solution of9-BBN (3.0 mL, 1.50 mmol) in THF. The mixture is slowly warmed to roomtemperature and stirred for two days. This solution is then added to aseparate flask containing 3-bromopyridine, Pd(PPh₃)₄ (57.7 mg, 0.05mmol), and potassium carbonate (276.2 mg, 2 mmol) in DMF (3.3 mL). Theresulting mixture is heated to 70° C. and stirred overnight. Thereaction is diluted with ethyl acetate and poured into water. Theaqueous layer is extracted three times with ethyl acetate, and thecombined organic extracts are washed with brine, dried with sodiumsulfate, and concentrated. The crude residue is purified by columnchromatography eluting with a gradient of 15-100% ethyl acetate inheptane to yield the desired product as a clear oil (130 mg, 59%). 1HNMR (CDCl₃, 400 MHz); δ 8.48 (d, 1H, J=4), 8.43 (s, 1H), 7.58 (d, 1H,J=8), 7.35-7.33 (m, 3H), 7.29-7.27 (m, 1.5H), 7.25-7.23 (m, 1.5H),7.19-7.18 (m, 2H), 7.05-7.03 (d, 1H, J=8), 4.87 (d, 1H, J=12), 4.69-4.66(d, 1H, J=12H), 4.36 (s, 1H), 3.74 (s, 3H), 3.57 (m, 1H), 3.18 (m, 1H),2.58 (t, 2H, J=4), 2.41 (m, 1H), 2.05 (m, 1H), 1.05 (s, 9H). Massspectrum (511.5; M+1).

Example 6N-hydroxy-N²-(3-hydroxypropyl)-N²-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinamide

Steps 1-2:(3R)-3-tert-butyl-4-[(3-methoxyphenyl)sulfonyl]morpholin-2-one

To a solution of N-(3 Methoxyphenylsulfonyl)D-tert-leucine (1.50 g, 4.98mmol) in DCM cooled to 0° C. with an ice-brine bath, DIC (1.54 mL, 9.95mmol) and DMAP (122 mg, 1.00 mmol) are added. The reaction mixture isstirred for 5 min at 0° C., then, 2-bromoethanol (562 μL, 7.96 mmol) isadded dropwise. The reaction mixture is allowed to slowly warm up to rt,then, stirred for 18 h. The white precipitate is filtered, then, thereaction mixture is concentrated in vacuo. The crude intermediate waspurified by silica gel chromatography eluting with 5-80% EtOAc/heptaneto obtain the desired intermediate (1.59 g, 78% yield). To a solution ofthe (R)-2-(3-Methoxy-benzenesulfonylamino)-3,3-dimethyl-butyric acid2-bromo-ethyl ester intermediate (1.59 g, 3.90 mmol) in DMF (19 mL),potassium carbonate (2.15 g, 15.6 mmol) is added, and the reactionmixture is heated at 70° C. for 2 h. The reaction mixture isbi-partitioned between diethyl ether and water. The organic layer isseparated, the aqueous layer is back-extracted with diethyl ether. Theorganic extracts are combined, washed with brine, dried over sodiumsulfate, and concentrated in vacuo to obtain the crude product as aviscous yellow oil. The crude intermediate is purified by silica gelchromatography eluting with 5-100% EtOAc/heptane to obtain the desiredcyclic lactone product (500 mg, 39% yield) and 310 mg of the ring-openedby-product (15% yield). Mass spectrum (328.2; M+1).

Steps 3-4:N-hydroxy-N²-(3-hydroxypropyl)-N²-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinamide

To a solution of(3S)-3-tert-butyl-4-[(3-methoxyphenyl)sulfonyl]morpholin-2-one (260 mg,0.79 mmol) in anhydrous DCM (2 mL), O-benzylhydroxylamine (358 μL, 3.07mmol) is added and the reaction mixture is stirred at rt for 30 min,then trimethylaluminum (2M in hexanes, 1.5 mL, 3.00 mmol) is addeddropwise under nitrogen. The resulting reaction mixture is stirred at rtfor 1 h. The reaction is quenched with pH7 phosphate buffer. Thereaction mixture is extracted with DCM, then the combined organicextracts are washed with brine, dried over sodium sulfate, concentratedin vacuo. The crude reaction mixture is purified by silica gelchromatography eluting with a gradient of 5-100% EtOAc/heptane to obtainthe desired O-benxylhydroxamide intermediate (541 mg, 100% yield). To adegassed solution of the O-benzylhydroxamide intermediate (100 mg, 0.22mmol) in methanol (2 mL), catalytic palladium on activated carbon (2 mg,0.022 mmol) is added, and the reaction mixture is stirred under hydrogenfor 1 h. The reaction mixture is filtered and concentrated in vacuo. Theresulting crude product is purified by a reverse-phase Gilson HPLC toobtain the desired product (45 mg, 56% yield). ¹H NMR (400 MHz,d₄-methanol) δ ppm 7.50-7.41 (m, 2H), 7.36 (m, 1H), 7.18 (m, 1H), 4.16(ddd, J=16, 12, 4 Hz, 1H), 3.98 (s, 1H), 3.95 (ddd, J=20, 16, 4 Hz, 1H),3.87 (s, 3H), 3.72 (ddd, J=20, 16, 4 Hz, 1H), 3.24 (ddd, J=16, 12, 4 Hz,1H), 1.08 (s, 9H). Mass spectrum (361.1; M+1).

Example 7

The following compound is prepared analogously to Example 6 startingfrom the requisite amino acid ester derivative.

Example R1 e/z 7-1 EtNH(CO)NH— M + H: 417.2

Other Embodiments

Other embodiments will be evident to those of skill in the art. Itshould be understood that the foregoing detailed description is providedfor clarity only and is merely exemplary. The spirit and scope of thepresent invention are not limited to the above examples, but areencompassed by the following claims.

1. A compound of formula (I)

wherein R₁ is cyano, (C₁-C₇)alkyl, amino, R₄—O—, (C₁-C₇)alkyl-NHC(O)—,R₅—C(O)NH—, R₆C(O)—, R₉—C(O)—O— or R₁₀—O—C(O)—, wherein R₄, R_(6,)R_(9,) and R₁₀ are independently hydrogen, (C₁-C₇)alkyl, mono- ordi-(C₁-C₇)alkylamino or aryl each of which is optionally substituted byone to five substituents selected from the group consisting of(C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxy and aryl; R₅ is hydrogen,(C₁-C₇)alkyl, (R₇)(R)N—, or (C₁-C₇)alkoxy; R₇ and R₈ are independentlyhydrogen, (C₁-C₇)alkyl, or aryl-(C₁-C₇)alkyl; R₂ is hydrogen, or(C₁-C₇)alkyl which is optionally substituted by one to threesubstituents selected from the group consisting of (C₁-C₇)alkyl,hydroxy, aryl, heterocyclyl, heteroaryl, (C₁-C₇)alkyl-O—C(O)—,di-(C₁-C₇)alkylamino-C(O)—, wherein each of aryl, heterocyclyl, andheteroaryl is further optionally substituted by (C₁-C₇)alkyl; or R₃ is(C₁-C₇)alkyl, or cycloalkyl; a pharmaceutically acceptable salt thereof;or an optical isomer thereof; or a mixture of optical isomers.
 2. Thecompound of claim 1, wherein R₁ is (C₁-C7)alkyl, R₄—O—, R₅—C(O)NH—, orR₉—C(O)—O—, wherein R₄ is (C₁-C₇)alkyl optionally substituted by one tothree halo, R₆ is hydrogen, (C₁-C₇)alkoxy, or mono-(C₁-C₇)-alkylamino,and R₉ is mono-(C₁-C₇)-alkylamino; R₂ is (C₁-C₇)alkyl optionallysubstituted by (C₁-C₇)alkyl-O—C(O)—, di-(C₁-C₇)alkylamino, or hydroxy;or R₂ is aryl-(C₁-C₇)alkyl-, heteroaryl-(C₁-C₇)alkyl-,heterocyclyl-(C₁-C₇)alkyl, wherein said heterocyclyl is optionallysubstituted by (C₁-C₇)alkyl; and R₃ is (C₁-C₇)alkyl; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.
 3. The compound of claim 1, wherein R₁is (C₁-C₇)alkoxy, R₅—C(O)—NH—, or R₉—C(O)—O—, wherein R₅ and R₉ is(C₁-C₇)alkylNH— or (C₁-C₇)alkoxy, R₂ is (C₁-C₇)alkyl; R₃ is(C₁-C₇)alkyl.
 4. The compound of claim 1, wherein R₁ is (C₁-C₇)alkoxy orR₅—C(O)—NH—, wherein R₅ is (C₁-C₇)alkylNH—; R₂ is (5-9 membered)heteroaryl-(C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl.
 5. A compound of formula(II)

Wherein R₁ is cyano, (C₁-C₇)alkyl, amino, R₄—O—, (C₁-C₇)alkyl-NHC(O)—,R₅—C(O)NH—, R₆C(O)—, R₉—C(O)—O— or R₁₀—O—(O)—, wherein R₄, R_(6,) R_(9,)and R₁₀ are independently hydrogen, mono- or di-(C₁-C₇)alkylamino,(C₁-C₇)alkyl or aryl each of which is optionally substituted by one tofive substituents selected from the group consisting of (C₁-C₇)alkyl,halo, hydroxyl, (C₁-C₇)alkoxy and aryl; R₅ is hydrogen, (C₁-C₇)alkyl or(R₇)(R₈)N—, or (C₁-C₇)alkoxy; R₇ and R₈ are independently hydrogen,(C₁-C₇)alkyl, or aryl-(C₁-C₇)alkyl; R₂ is hydrogen, (C₁-C₇)alkyl, whichis optionally substituted by one to three substituents selected from thegroup consisting of (C₁-C₇)alkyl, hydroxy, aryl, heterocyclyl,heteroaryl, (C₁-C₇)alkyl—O—C(O)—, di-(C₁-C₇)alkylamino-C(O)—, whereineach of aryl, heterocyclyl, and heteroaryl is further optionallysubstituted by (C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl or cycloalkyl; or apharmaceutically acceptable salt thereof; or an optical isomer thereof;or a mixture of optical isomers.
 6. The compound of claim 5, wherein R₁is (C₁-C₇)alkyl, R₄—O—, or R₅—C(O)NH—, wherein R₄ is (C₁-C₇)alkyloptionally substituted by one to three halo, R₅ is hydrogen ormono-(C₁-C₇)-alkylamino; R₂ is (C₁-C₇)alkyl optionally substituted by(C₁-C₇)alkyl-O—C(O)—, di-C₁-C₇)-alkylamino-C(O)—, hydroxy; or R₂ isaryl-(C₁-C₇)alkyl-, heteroaryl-(C₁-C₇)alkyl-, heterocyclyl-(C₁-C₇)alkyl,wherein said heterocyclyl is optionally substituted by (C₁-C₇)alkyl; R₃is (C₁-C₇)alkyl; or a pharmaceutically acceptable salt thereof; or anoptical isomer thereof; or a mixture of optical isomers.
 7. The compoundof claim 5, wherein R₁ is (C₁-C₇)alkoxy, R₅—C(O)—NH—, or R₉—C(O)—O—,wherein R₅ and R₉ is (C₁-C₇)alkylNH— or (C₁-C₇)alkoxy; R₂ is(C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl.
 8. The compound of claim 5, wherein R₁is (C₁-C₇)alkoxy or R₅—C(O)—NH—, wherein R₅ is (C₁-C₇)alkylNH—; R₂ is(5-9 membered) heteroaryl-(C₁-C₇)alkyl; R₃ is (C₁-C₇)alkyl.
 9. Acompound of formula (III)

Wherein R₁ is cyano, nitro, halo, alkyl, amino, R₄—O—, R₅—C(O)NH—, orR₆C(O)—, wherein R₄, R₅, and R₆ are independently alkyl or aryl each ofwhich is optionally substituted by one to five substituents selectedfrom the group consisting of (C₁-C₇)alkyl, halo, hydroxyl, (C₁-C₇)alkoxyand aryl, or R₅ is alkoxy or (C₁-C₇)alkylamino; R₂ is alkyl,aryl-alkyl-, or heteroaryl-alkyl-, (5-9membered)heterocyclyl-(C₁-C₇)alkyl, mono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl,or di-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or a pharmaceutically acceptablesalt thereof; or an optical isomer thereof; or a mixture of opticalisomers.
 10. The compound of claim 9, wherein R₁ is nitro, cyano, halo,(C₁-C₇)alkyl, R₄—O—, R₅—C(O)NH—, or R₆C(O)—, wherein R₄, R₅ and R₆ areindependently (C₁-C₇)alkyl, phenyl, biphenyl, naphthyl, ortetrahydronaphthyl each of which is optionally substituted by one tofive substituents selected from the group consisting of (C₁-C₇)alkyl,halo, hydroxyl and (C₁-C₇) alkoxy; R₂ is (C₁-C₇)alkyl,(C₆-C₁₀)aryl-(C₁-C₇)alkyl, or (5-9 membered) heteroaryl-(C₁-C₇)alkyl,(5-9 membered) heterocyclyl-(C₁-C₇)alkyl, ormono-(C₁-C₇)alkylamino-(C₁-C₇)alkyl, ordi-(C₁-C₇)alkylamino-(C₁-C₇)alkyl; or R₅ is alkoxy or (C₁-C₇)alkylamino;or a pharmaceutically acceptable salt thereof; or an optical isomerthereof; or a mixture of optical isomers.
 11. (canceled)
 12. (canceled)13. A method of inhibiting activity of MMP-9, and/or MMP-12 and/orMMP-13 in a subject, comprising: administering to the subject atherapeutically effective amount of the compound according to claim 1.14. A method of treating a disorder or a disease in a subject mediatedby MMP-9, and/or MMP-12 and/or MMP-13, comprising: administering to thesubject a therapeutically effective amount of the compound according toclaim
 1. 15. The method of claim 14, wherein the disorder or the diseaseis selected from the group consisting of Alport syndrome, asthma,rhinitis, chronic obstructive pulmonary diseases (COPD), arthritis,atherosclerosis and restenosis, cancer invasion and metastasis, diseasesinvolving tissue destruction, loosening of hip joint replacements,periodontal disease, fibrotic disease, infarction and heart disease,liver and renal fibrosis, endometriosis, diseases related to theweakening of the extracellular matrix, heart failure, aortic aneurysms,CNS related diseases, hematological disorders.
 16. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of thecompound of claim 1 and one or more pharmaceutically acceptablecarriers.
 17. A pharmaceutical compositions comprising: atherapeutically effective amount of the compound according to claim andone or more therapeutically active agents selected from AT₁ receptorantagonists, alpha-adrenoceptor antagonists, rennin inhibitors, ACEinhibitors, endothelin receptor antagonists, ACE/NEP dual inhibitors,ECE inhibitors, NEP inhibitors, vasopressin antagonists, aldosteronereceptor antagonists, aldosterone inhibitors, angiotensin vaccine andurotensin II receptor antagonists. 18-23. (canceled)